Citations

We analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic mutations after whole genome sequencing to a depth of more than 200×. Typically, brains had 20 to 60 detectable single-nucleotide mutations, but ~6% of brains harbored hundreds of somatic mutations. Hypermutability was associated with age and damaging mutations in genes implicated in cancers and, in some brains, reflected in vivo clonal expansions. Somatic duplications, likely arising during development, were found in ~5% of normal and diseased brains, reflecting background mutagenesis. Brains with autism were associated with mutations creating putative transcription factor binding motifs in enhancer-like regions in the developing brain. The top-ranked affected motifs corresponded to MEIS (myeloid ectopic viral integration site) transcription factors, suggesting a potential link between their involvement in gene regulation and autism.

10022 Background: nab-Sirolimus (formerly know ABI-009 and nab-rapamycin) is a novel human albumin-bound preparation of sirolimus, a potent mTOR inhibitor. We report results of a Phase I study of ABI-009 alone and in combination with irinotecan and temozolomide in children with relapsed/refractory solid or CNS tumors. Methods: Patients (age 1-21 years) with relapsed/refractory solid or CNS tumors were eligible. Using a rolling 6 design, ABI-009 was administered intravenously as a single agent on Days 1 and 8 of cycle 1 (cycle = 21d), then subsequent cycles ABI-009 was administered in combination with temozolomide (125 mg/m2/dose, maximum 250 mg/dose) orally once daily x 5 on Days 1-5 and irinotecan 90 mg/m2/dose orally once daily x 5 on Days 1-5. Three dose levels (DL) of ABI-009 were investigated (DL1: 35mg/m2/dose, DL-1: 20mg/m2/dose, and DL-2: 15mg/m2/dose). The maximum tolerated dose (MTD) or Recommended Phase 2 Dose (RP2D) was established based on dose limiting toxicity (DLT) observed during Cycle 1 and 2. At the RP2D, additional patients were enrolled for pharmacokinetics (PK). Results: 33 patients were enrolled (32 eligible and 1 ineligible); 11 did not experience DLT but were not evaluable for toxicity due to progressive disease or physician decision to discontinue protocol therapy prior to completion of cycle 2; 17 [median age 13 (2-20) years] were evaluable for determination of MTD during dose escalation, 6 were enrolled on the PK cohort, of which 3 were evaluable to toxicity. At DL1, 2/5 patients experienced DLT (thrombocytopenia during cycle 1 (n = 1) and cycle 2 (n = 1)); at DL-1, 2/6 patients experienced DLT (thrombocytopenia in cycle 1); at DL-2, 1/6 patients experienced DLT (thrombocytopenia in cycle 1). PK expansion enrolled at DL-2 and 1/3 participants evaluable for toxicity had a DLT (mucositis). Overall, at DL-2, 2/9 patients (22%) had DLT. One patient with Ewing Sarcoma had a partial response and remained on study for 35 cycles; Patients (one each) with Ewing Sarcoma, Wilms Tumor, and Pineoblastoma had stable disease, ranging from 3-6 cycles. Conclusions: Thrombocytopenia was dose limiting for ABI-009 alone and in combination with temozolomide and irinotecan. The MTD for ABI-009 is 15mg/m2/dose days 1 and 8 in combination with 5 daily doses of temozolomide 125 mg/m2/dose and oral irinotecan 90 mg/m2/dose. One patient had a partial response, 3 patients had prolonged stable disease. Pharmacokinetics and pharmacodynamics are pending and will inform future trials. Clinical trial information: NCT02975882.

AbstractBackgroundChildren with diffuse intrinsic pontine gliomas (DIPG) have a dismal prognosis. Adavosertib (AZD1775) is an orally available, blood-brain barrier penetrant, Wee1 kinase inhibitor. Preclinical efficacy against DIPG is heightened by radiation induced replication stress.MethodsUsing a rolling six design, 7 adavosertib dose levels (DLs) (50 mg/m2 alternating weeks, 50 mg/m2 alternating with weeks of every other day, 50 mg/m2, then 95, 130, 160, 200 mg/m2) were assessed. Adavosertib was only given on days of cranial radiation therapy (CRT).The duration of CRT (54 Gy over 30 fractions; 6 weeks) constituted the dose limiting toxicity (DLT) period. Endpoints included tolerability, pharmacokinetics, overall survival (OS) and peripheral blood γH2AX levels as a marker of DNA damage.ResultsA total of 46 eligible patients with newly diagnosed DIPG [median (range) age 6 (3–21) years; 52% female] were enrolled. The recommend phase 2 dose (RP2D) of adavosertib was 200 mg/m2/d during days of CRT. Dose limiting toxicity included ALT elevation (n = 1, DL4) and neutropenia (n = 1, DL7). The mean Tmax, T1/2 and Clp on Day 1 were 2 h, 4.4 h, and 45.2 L/hr/m2, respectively. Modest accumulation of adavosertib was observed comparing day 5 versus day 1 AUC0-8h (accumulation ratio = 1.6). OS was 11.1 months (95% CI: 9.4, 12.5) and did not differ from historical control.ConclusionAdavosertib in combination with CRT is well tolerated in children with newly diagnosed DIPG, however, compared to historical controls, did not improve OS. These results can inform future trial design in children with high-risk cancer.

Abstract Introduction: Selinexor is a first-in-class, central nervous system (CNS) penetrant, oral inhibitor of exportin 1 (XPO1), the sole nuclear exporter of many key tumor suppressors. Selinexor is FDA-approved for refractory multiple myeloma and DLBCL and has been evaluated in a phase 1 trial in children with leukemia. We report a phase 1 trial of selinexor in children and adolescents with recurrent CNS and solid tumors, including lymphoma (NCT02323880). Methods: A rolling-six design was used to evaluate selinexor (10 or 25 mg tablets) administered twice or once weekly during a 28-day cycle. Dose determination was based on protocol-defined dose limiting toxicity (DLT) using CTCAEv4 during cycle 1. First dose pharmacokinetics (PK) were performed. Results: 43 subjects were enrolled (17 males); median (range) age was 15 (6-20) years. 27 (63%) had CNS tumors, most commonly high-grade glioma (n=12); 16 (37%) had extracranial solid tumors. 42 were evaluable for DLT. At the starting dose (35 mg/m2/dose, twice weekly), no DLTs were observed in 6 subjects, however, 2 subjects had unexpected late myelosuppression delaying initiation of cycle 2. The dosing schedule was amended to twice weekly for 3 weeks followed by a 1 week break. 12 subjects received 35 mg/m2/dose; 4 experienced DLTs [grade 3 fatigue (n=2), grade 3 thrombocytopenia (n=1), or grade 3 ALT increase (n=1)]. The dose was de-escalated to 20 mg/m2/dose, 3 weeks on, 1 week off. 12 subjects enrolled; 3 experienced a DLT [grade 3 increased AST/ALT, acute reversible neurologic changes, or neutropenia (each n=1)]. At the 20 mg/m2 (n=12) and 35 mg/m2 (n=19) dose levels, respectively, the mean ± SD Cmax (ng/ml) was 324±116 and 535±174, and AUC (hr•ng/ml) was 3092 ± 842 and 5156 ± 1227. This was comparable to PK in adults receiving 35 and 50 mg/m2. Based on a desire to achieve a higher Cmax and avoid breaks in schedule, and emerging evidence for similar effectiveness with decreased toxicity in adults receiving continuous once weekly dosing, we evaluated a dosing schedule with once weekly dosing for all 4 weeks of each cycle. At the initial dose level (45 mg/m2 weekly), 2 of 6 subjects had DLTs [prolonged grade 2 thrombocytopenia or grade 3 seizure in a primary CNS tumor patient]. Six subjects received 35 mg/m2/dose once weekly; 1 DLT [grade 3 thrombocytopenia] was observed. Non-dose-limiting toxicity (Grade ≥2 occurring in >10% of subjects during cycle 1) included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. Subjects received a median (range) of 1 (1-9) cycle; 13 received 2-3 cycles, and 6 received 5-9 cycles. Conclusions: Selinexor-related toxicities were primarily hematological and gastrointestinal. The maximum tolerated dose (MTD) of selinexor in children and adolescents with recurrent solid and CNS tumors is 20 mg/m2/dose twice weekly for 3 weeks followed by one week off. On a continuous once weekly schedule, the MTD and recommended phase 2 starting dose of selinexor is 35 mg/m2/dose. Citation Format: Adam L. Green, Charles G. Minard, Xiaowei Liu, Joel M. Reid, Kerice Pinkney, Stephan Voss, Marvin D. Nelson, Elizabeth Fox, Brenda J. Weigel, Julia Glade Bender. Phase 1 trial of selinexor in children and adolescents with recurrent/refractory solid and CNS tumors (ADVL1414): A Children’s Oncology Group Phase 1 Consortium trial [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P162.

10019 Background: Pevonedistat (PEV), a first in class inhibitor of NEDD8 activating enzyme (NAE), prevents the activation of Cullin-RING ligases (CRL) necessary for proteasome mediated degradation of key regulatory proteins important in cell survival. In adults with solid tumors, the maximum tolerated dose (MTD) in combination with chemotherapy is 20-25 mg/m2. Antitumor activity of PEV has been demonstrated in preclinical models of childhood cancer. In vivo additive activity has been demonstrated for PEV in combination with IRN and alkylating agents. The objectives of this study are to determine the MTD and recommended Phase 2 dose of PEV in combination with IRN and TMZ and describe the toxicities, pharmacokinetic (PK), and pharmacodynamics (PD) properties of this combination. Methods: We conducted a phase 1 trial of PEV in combination with IRN and TMZ in pediatric patients (pts) with recurrent or refractory solid tumors and brain tumors. During cycle 1, PEV was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50mg/m2) and TMZ (orally, 100mg/m2), on days 8-12 of a 28 day cycle. In subsequent cycles, PEV was administered on days 1, 3, and 5, with IRN and TMZ on days 1-5 of a 21 day cycle. Dose escalation was determined using the Rolling 6 Design. Results: 30 pts enrolled. All pts were eligible and evaluable for cycle 1 dose limiting toxicity (DLT) assessment. Median (range) age was 13 (1-21) years; 19 (63%) were male. Eleven pts had brain tumors, and 19 pts had solid tumors. Six pts each enrolled on PEV dose levels (DL) 1 (15mg/m2), 2 (20mg/m2), 3 (25mg/m2) and 4 (35mg/m2) as well as an expanded PK cohort at DL4. Cycle 1 grade 3/4 toxicities include lymphopenia (n = 5), leukopenia (n = 4), neutropenia (n = 2), elevated ALT (n = 2), elevated AST (n = 1), diarrhea (n = 1), flu-like symptoms (n = 1). The most frequent non-dose limiting AEs in cycle 1 were anemia (87%), WBC decreased (77%), nausea (57%), diarrhea (53%), ALT increased (50%), AST increased (50%), and vomiting (50%). PK analyses showed the mean area under the curve at the 25 mg/m2 dose level on day 8 (in combination with irinotecan and temozolomide) was 1300 hr•ng/mL, half-life (T ½) was 5-6 hours, time to maximum concentration (Tmax) was 1 hour, and mean clearance was 20 L/hr/m2. There were 3 DLTs, 2 of which were related to protocol therapy (diarrhea and thrombocytopenia), among 12 patients on DL4. Thus the MTD was not exceeded at any dose level. PK at the 25 mg/m2 dose level are comparable to those in adult patients. PK from the 12 patients on DL4 (35mg/m2) as well as responses of all patients are pending. Conclusions: PEV in combination with IRN and TMZ is well tolerated in children with solid or brain tumors. PEV PK was not altered by the addition of irinotecan and temozolomide. Further PK and PD analyses are ongoing to establish the recommended phase 2 dose. Clinical trial information: NCT03323034.

10018 Background: Outcomes for children with relapsed/refractory (R/R) AML and MDS are poor and new therapies are needed. Pevonedistat is an inhibitor of the NEDD-8 activating enzyme, a key regulator of the ubiquitin proteasome system that is responsible for protein turnover, cell growth and survival. In preclinical models, pevonedistat was synergistic with cytarabine (AraC) and azacitidine (aza). The combination of pevonedistat + aza in adults with AML demonstrated improved responses compared to either single agent. We evaluated the feasibility, toxicity and pharmacokinetics (PK) of pevonedistat in combination with aza, fludarabine, AraC (Aza-FLA) in children with R/R AML and MDS. Methods: Pevonedistat 20 mg/m2, IV days 1, 3, 5, the recommended adult dose, was administered in combination with aza (75 mg/m2, days 1-5), fludarabine (30 mg/m2, days 6-10), and AraC (2000 mg/m2, days 6-10). Intrathecal AraC was administered at the start of therapy and additional doses given to patients with CNS leukemia. If < 33% of the initial 6 enrolled patients experienced dose limiting toxicity (DLT) during cycle 1 the regimen would be considered tolerable and 6 additional patients could enroll to further assess tolerability and PK. Pevonedistat PK was determined during cycle 1 following doses 1 and 5. Response was evaluated after cycle 1. Results: A total of 12 patients were enrolled, median age was 13 years (range 1-21). All patients received prior chemotherapy, median number of prior regimens was 2 (range 1-5) and 3 (25%) patients had prior hematopoietic stem cell transplant. Diagnoses were AML NOS (n = 10, 83%), acute monocytic leukemia (n = 1), and therapy related AML (n = 1). One of the initial 6 patients had DLTs (hypertension, GGT elevation, and proteinuria); pevonedistat 20 mg/m2 + Aza-FLA was considered tolerable. Six additional patients were enrolled, two had DLTs (weight loss, hypoxia). Overall, 3/12 (25%) of patients experienced DLTs. As expected, using the intensive Aza-FLA backbone, myelosuppression, electrolyte abnormalities, and hepatic transaminase elevation were common. Day 1 PK parameters (n = 12, mean±SD) were: Cmax= 223±91 ng/mL, AUC0-24h= 892±216 ng/hr/mL, T1/2=4.3±1.2 hours, CL = 23.2±6.9 L/hr/m2. PK parameters were similar following doses 1 and 5, for patients < 12 (n = 6) and ≥ 12 (n = 6) years, and to adult PK profiles. Ten patients were evaluable for response. The overall response rate was 30% (95% CI: 7,75) with 3 patients achieving a CR with incomplete hematologic recovery (CRi). Conclusions: Pevonedistat 20 mg/m2 combinedwith Aza-FLA was tolerable in children with R/R AML. The toxicity of the regimen was similar to other intensive AML regimens. PK parameters were similar among the two age groups and were comparable to adults. Within the confines of a phase I study, there was limited anti-leukemic activity of the combination of pevonedistat +Aza-FLA in R/R AML. Clinical trial information: NCT03813147.

AbstractBackgroundPrexasertib (LY2606368) is a novel, second‐generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum‐tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors.MethodsPrexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28‐day cycle. Four dose levels, 80, 100, 125, and 150 mg/m2, were evaluated using a rolling‐six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity.ResultsThirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2‐20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose‐limiting toxicities. Common cycle 1, drug‐related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80‐150 mg/m2 dose range.ConclusionsAlthough the MTD of prexasertib was not defined by this study, 150 mg/m2 administered i.v. on days 1 and 15 of a 28‐day cycle was determined to be the RP2D.

AbstractBackgroundEntinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies.MethodsA rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28‐day cycle. PK and PD studies were performed.ResultsTwenty‐one eligible patients’ median (range) age was 14 years (6‐20). Six subjects were treated at 3 mg/m2dose level and 15 were treated in 4 mg/m2dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose‐limiting toxicity (DLT) was observed at either dose level. A three‐fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses.ConclusionsEntinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m2orally administered once weekly.

Background: Despite improvements in outcomes for children with B- and T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (B-ALL, T-ALL, B-LLy and T-LLy), the outcome of patients with primary resistant or relapsed disease remains very poor, particularly for children with second or greater relapses and with T-cell disease. Deregulation of cell cycle machinery is essential for both the induction and progression of ALL (Sicinska et al. Cancer Cell 4:451-61, 2003). Additionally, targeting cell cycle regulators CDK4 and 6 efficiently suppresses ALL growth and disease progression in vivo (Sawei et al. Cancer Cell 22:452-65, 2012) and this effect is augmented by conventional chemotherapy. These data provided the rationale for investigating the CDK4/6 inhibitor palbociclib in relapsed/refractory ALL and LLy. Preliminary results from the ongoing Children's Oncology Group (COG) AINV18P1 trial are reported. Methods: Patients aged 1-30 years with first or greater isolated or combined marrow relapses of T-ALL or T-LLy and second or greater relapses of B-ALL or B-LLy are eligible for COG AINV18P1 (NCT03792256). Patients with refractory disease with at least 2 prior induction attempts or first relapse refractory to at least one prior re-induction attempt are also eligible. This is a 2-part study conducted at selected COG sites. In Part 1 of the study (dose determination), palbociclib was administered orally once daily for 21 consecutive days, first as a single agent (days 1-3) and subsequently in combination with 4-drug re-induction chemotherapy (Table 1). Study treatment consisted of a single cycle of therapy. A starting palbociclib dose of 50 mg/m2/dose was explored with one dose de-escalation (35 mg/m2/dose) using the rolling six design to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Part 2 (expansion cohort) is accruing 6 additional patients (pts) at the MTD for further assessment of the safety and feasibility of combination therapy. Dose-limiting toxicities (DLTs), defined as hematologic and non-hematologic toxicities exceeding baseline toxicities observed with re-induction chemotherapy alone, are assessed throughout the treatment cycle. The primary aims of the study are safety, determination of the MTD/RP2D and assessment of palbociclib pharmacokinetics (PK). Secondary aims are assessment of the biological and preliminary clinical activity of combination therapy in this patient population. Results: As of June 30, 2020, 8 pts have enrolled; 6 in Part 1 and 2 in Part 2. All 6 pts in Part 1 completed one full cycle (32 days) of protocol therapy. The median (range) age of pts is 10 (6-21) years and 62% are male (Table 2). Three pts had T-ALL, 4 B-ALL and 1 T-LLy. Pts received a median (range) of 2 (1-6) prior chemotherapy regimens and 2 pts underwent prior allogeneic stem cell transplant. All 6 pts in Part 1 experienced grade 3-4 toxicities, most commonly hematologic: anemia (3 pts), neutropenia (5 pts) and thrombocytopenia (4 pts). Three pts had grade 3 infections and one pt had grade 3 hyperbilirubinemia, which resolved. No hematologic or non-hematologic DLTs were observed at the 50 mg/m2/dose of palbociclib in Part 1 and accrual to the expansion phase of the trial at this dose continues. PK and pharmacodynamic studies assessing cell cycle inhibition are also ongoing. Conclusions: Palbociclib in combination with 4-drug re-induction chemotherapy is safe and well tolerated in children and young adults with relapsed/refractory ALL and LLy. Further assessment of the feasibility and activity of combination therapy is ongoing in the expansion phase of this trial. Disclosures Raetz: Celgene: Other: DSMB member; Pfizer: Other: Institutional research funding. Teachey:La Roche: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sobi: Consultancy. Norris:Merck: Other: Travel funding. Gore:Amgen, Novartis, Roche: Membership on an entity's Board of Directors or advisory committees. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. OffLabel Disclosure: This study includes off-label use of palbociclib in children and young adults with relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma.